The long-term goal of the research supported by the paternal grant is to analyze developmental regulation of neuronal migration. The serine-threonine kinase cdk5, a focus of interest of the parental laboratory, is one of the key genes in this process. Ablation of cdk5, or its regulatory activators, causes disruption of mouse brain structure, thus identification of cdk5 substrates may provide us with molecules with crucial activities during brain development. Cdk5 interacts with several signaling networks involved in neuronal migration. Among several substrates, cdk5 phosphorylates Nudel, a LIS1/dynein interacting protein. Human brain organization is also disrupted in case of neuronal migration disorders, as lissencephaly (i.e. "smooth brain"), which may be the result of mutations in LIS1. The Reiner laboratory research is focused on the functional analysis of genes involved in lissencephaly. The premise that underlies the collaboration between Dr. Tsai's and Dr. Reiner's laboratory is that combining of knowledge and expertise from both laboratories can enhance significantly the research in each individual laboratory. The Reiner laboratory has gained expertise in understanding protein domains through computational and experimental analysis. The Tsai laboratory has integrated and methods of in vivo analysis to neuronal development. The specific objectives of the current grant are: 1. Fine mapping of the interaction between Nudel and LIS1: the Nudel interphase. 2. Fine mapping of the interaction between Nudel and LIS1: the LIS1 interphase. 3. Determination of the in vivo functions of LIS1 phosphorylation mutants that affect its interaction with Nudel, and Nudel mutants with aberrant interactions with LIS1, in migrating neurons in the cortex. The combination of skills from both laboratories will allow elucidating the molecular interphase of NudeI-LIS1 interactions and their importance during brain development. This research will be done primarily in The Weizmann Institute, Israel, in collaboration with Li-Huei Tsai as an extension of NIH grant # ROINS037007. [unreadable]